Diaryl benzo pyridine derivative, and preparation and use thereof

[0041] Embodiment 1: Synthesis of diarylbenzopyrimidine derivatives (method 1)

[0042] Under the protection of an inert gas, add substituted phenol (or aniline, etc.) 2 CO 3 , control the temperature at 80-120°C, and stir for 8-12 hours. After TLC showed that the reaction was finished, the K 2 CO 3, the filtrate was poured into cold water, the precipitated solid was filtered and dried. Decolorized by activated carbon and recrystallized from toluene to obtain the desired compound.

[0043] With different 4-chlorobenzopyrimidine derivatives and different substituted phenols (or aniline, etc.). The target compound was prepared respectively by the above method, and some results are as follows:

[0044] Under N2 protection, 2-methylphenol (4.2mmol) was added to 30mL of anhydrous DMF, stirred to dissolve it, and then 2-(4-cyanoanilino)-4-chlorobenzopyrimidine (3.5mmol ), stirred for 10min to dissolve it, added anhydrous K 2 CO 3 (0.021mol), the temperature was controlled at 90-100°C, and the reaction was stirred for 8h. TLC showed that the reaction was complete, and K was removed by filtration 2 CO 3 , The filtrate was poured into 300mL cold water, solids were precipitated, filtered, and dried to obtain solids. Decolorized by activated carbon and recrystallized from toluene to obtain the desired compound.

[0045]

[0046] Brown powdery solid, yield 75%; melting point: 197.3-197.4°C; 1 H NMR (DMSO-d 6 ) δ (ppm) 2.16 (s, 3H, CH 3 ), 7.30-7.44 (m, 4H, Ar`H), 7.49 (td, 1H, J=7.6Hz, J`=1.2Hz, ArH 7 ), 7.56(d, 2H, J=8.8Hz, Ar``H 2，6 ), 7.72 (d, 1H, J=8.4Hz, ArH 6 ), 7.86(d, 2H, J=8.8Hz, Ar``H 3，5 ), 7.90 (td, 1H, J=7.6Hz, J`=1.2Hz, ArH 8 ), 8, 27 (dd, 1H, J=8.0Hz, J`=0.8Hz, ArH 9 ), 10.04(s, 1H, NH).

[0047] 13 C NMR (DMSO-d 6 ) δ (ppm) 16.4 (CH 3 ), 102.8 (Ar``C 4 ), 112.2 (ArC 5 ), 118.9 (2C, Ar``C 2，6 ), 120.0(CN), 122.9(ArC 6 ), 124.2 (Ar`C 6 ), 124.8 (ArC 7 ), 125.9 (ArC 9 ), 126.7 (Ar`C 4 ), 128.0 (Ar`C 5 ), 130.7 (Ar`C 3 ), 131.9 (ArC 8 ), 133.1 (Ar`C 2 ), 135.4 (2C, Ar``C 3，5 ), 145.4 (Ar``C 1 ), 151.4 (Ar`C 1 ), 153.1 (ArC 10 ), 155.7 (ArC 2 ), 167.2 (ArC 4 ).MS(ESI)m/z353(M + +1).

[0048]

[0049] The operation is the same as above. Yellow needle-like crystals, yield 85%; melting point: 267.3-267.6°C; 1 HNMR (DMSO-d 6 ) δ (ppm) 7.41 (d, 2H, J = 6.8Hz, Ar``H 2，6 ), 7.47(t, 1H, J=7.2Hz, ArH 7 ), 7, 61 (d, 2H, J=8.8Hz, Ar`H 2，6 ), 7.71-7.75 (m, 3H, ArH 6 +Ar``H 3，5 ), 7.88 (td, 1H, J=8.4Hz, J`=1.2Hz, ArH 8 ), 7.94 (d, 2H, J=8.4Hz, Ar`H 3，5 ), 8.21 (d, 1H, J=8.4Hz, ArH 9 ), 10.02(s, 1H, NH).

[0050] 13 C NMR (DMSO-d 6 )δ (ppm) 103.0 (Ar``C 4 ), 112.5 (ArC 5 ), 118.8 (2C, Ar``C 2，6 ), 119.0 (2C, Ar`C 2，6 ), 120.0 (CN), 124.2 (Ar`C 4 ), 124.8 (ArC 6 ), 125.2 (2C, Ar`C 3，5 ), 126.0 (ArC 7 ), 133.1 (ArC 9 ), 133.2 (2C, Ar``C 3，5 ), 135.5 (ArC 8 ), 145.3 (Ar``C 1 ), 152.2 (ArC 10 ), 153.1 (Ar`C 1 ), 155.4 (ArC 2 ), 167.4 (ArC 4 ).

[0051] MS (ESI) m/z 417 (M + +1).

[0052]

[0053] The operation is the same as above. White needle-like solid, yield 98.3%; melting point: 219.7-220.3°C; 1 H NMR (DMSO-d 6 ) δ (ppm) 2.39 (s, 3H, CH 3 ), 7.18-7.22 (m, 3H, Ar`H), 7.43 (d, 1H, J=7.6Hz, Ar`H), 7.48 (td, 1H, J=8.0Hz, J`=1.2Hz, ArH 7 ), 7.59 (d, 2H, J=8.4Hz, Ar``H 2，6 ), 7.72 (d, 1H, J=8.4Hz, ArH 6 ), 7.88 (td, 1H, J=7.2Hz, J`=1.2Hz, ArH 8 ), 7.93 (d, 2H, J=8.4Hz, Ar``H 3，5 ), 8.22 (dd, 1H, J=8.4Hz, J`=1.2Hz, ArH 9 ), 10.03(s, 1H, NH). 13 C NMR (DMSO-d 6 ) δ (ppm) 20.8 (CH 3 ), 102.3 (Ar``C 4 ), 112.0 (ArC 5 ), 118.4 (2C, Ar``C 2，6 ), 119.0(CN), 119.4(ArC 6 ), 122.4 (Ar`C 6 ), 123.6 (Ar`C 2 ), 124.1 (ArC 7 ), 125.3 (ArC 9 ), 126.5 (Ar`C 4 ), 129.5 (Ar`C 5 ), 132.6 (2C, Ar``C 3，5 ), 134.8 (ArC 8 ), 139.6 (Ar`C 3 ), 144.8 (Ar``C 1 ), 152.3 (ArC 10 ), 152.5 (Ar`C 1 ), 155.0 (ArC 2 ), 167.1 (ArC 4 ).

[0054] MS (ESI) m/z 353 (M + +1).

[0055]

[0056] The operation is as above. White flocculent solid, yield 89.1%; melting point: 218.2-218.4°C; 1 H NMR (DMSO-d 6 ) δ (ppm) 3.83 (s, 3H, CH 3 O), 7.08(d, 2H, J=6.8Hz, Ar`H 3，5 ), 7.32 (d, 2H, J=6.8Hz, Ar`H 2，6 ), 7.47 (td, 1H, J=8.0Hz, J`=0.8Hz, ArH 7 ), 7.59 (d, 2H, J=8.8Hz, Ar``H 2，6 ), 7.71 (d, 1H, J=8.4Hz, ArH 6 ), 7.87 (td, 1H, J=8.4Hz, J`=1.2Hz, ArH 8 ), 7.95 (d, 2H, J=8.4Hz, Ar``H 3，5 ), 8, 21 (dd, 1H, J=8.4Hz, J`=1.2Hz, ArH 9 ), 9.99(s, 1H, NH). 13 C NMR (DMSO-d 6 ) δ (ppm) 56.0 (CH 3 O), 102.9 (Ar``C4), 112.6 (ArC 5 ), 115.3 (2C, Ar`C 3，5 ), 119.0 (2C, Ar``C 2，6 ), 120.1 (CN), 123.5 (2C, Ar`C 2，6 ), 124.2 (ArC 6 ), 124.7 (ArC 7 ), 125.9 (ArC 9 ), 133.2 (ArC 8 ), 135.3 (2C, Ar``C 3，5 ), 145.4 (Ar``C 1 ), 146.2 (Ar`C 1 ), 153.0 (ArC 10 ), 155.6 (Ar`C 4 ), 157.6 (ArC 2 ), 167.9 (ArC 4 ).

[0057] MS (ESI) m/z 369 (M + +1).

[0058] Example 2: Synthesis of diarylbenzopyrimidine derivatives (method 2)

[0059] Mix 2-methoxyphenol and 2-chlorobenzopyrimidine derivatives together, heat to 150-210°C until the reactants are completely melted, and react for 1 hour. TLC showed that after the reaction was completed, it was dissolved in DMF, decolorized by activated carbon, filtered, and the filtrate was poured into cold water, and the precipitated solid was filtered and dried. Recrystallization from toluene afforded the desired compound.

[0060]

[0061] White flocculent solid, yield 82.9%; melting point: 220.0-220.5°C; 1 H NMR (DMSO-d 6 ) δ (ppm) 3.73 (s, 3H, CH 3 O), 7.10(td, 1H, J=7.6Hz, J`=1.6Hz, Ar`H 6 ), 7.30 (dd, 1H, J=8.4Hz, J`=1.2Hz, Ar`H 3 ), 7.35-7.41 (m, 2H, Ar`H 4，5 ), 7.47 (td, 1H, J=8.0Hz, J`=0.8Hz, ArH 7 ), 7.56(d, 2H, J=8.8Hz, Ar``H 2，6 ), 7.71 (d, 1H, J=8.4Hz, ArH 6 ), 7.84(d, 2H, J=8.8Hz, Ar``H 3，5 ), 7.89 (td, 1H, J=8.4Hz, J`=1.2Hz, ArH 8 ), 8, 22 (d, 1H, J=8.4Hz, ArH 9 ), 10.06(s, 1H, NH).

[0062] 13 C NMR (DMSO-d 6 ) δ (ppm) 55.8 (CH 3 O), 102.3 (Ar``C 4 ), 111.6 (ArC 5 ), 113.4 (Ar`C 3 ), 118.3 (2C, Ar``C 2，6 ), 119.5(CN), 121.0(ArC 6 ), 123.1 (Ar`C 5 ), 123.8 (ArC 7 ), 124.2 (Ar`C 6 ), 125.4 (ArC 9 ), 127.2 (Ar`C 4 ), 132.6 (2C, Ar``C 3，5 ), 134.9 (ArC 8 ), 140.9 (Ar``C 1 ), 144.9 (Ar`C 1 ), 151.1 (ArC 10 ), 152.6 (Ar`C 2 ), 155.2 (ArC 2 ), 166.8 (ArC 4 ).

[0063] MS (ESI) m/z 367 (M + -1).

[0064]

[0065] The operation is as above. White powder not solid, yield 89.6%; melting point: 230.7-231.9°C; 1 H NMR (DMSO-d 6 )δ (ppm) 7.38-7.43 (m, 3H, Ar``H 2，6 +Ar`H 4 ), 7.48(t, 1H, J=7.6Hz, ArH 7 ), 7.55-7.59 (m, 4H, Ar`H 3，5 +Ar`H 2，6 ), 7.72 (d, 1H, J=8.0Hz, ArH 6 ), 7.87-7.91 (m, 3H, Ar``H 3，5 +ArH 8 ), 8, 23 (d, 1H, J=8.0Hz, ArH 9 ), 10.04(s, 1H, NH).

[0066] 13 C NMR (DMSO-d 6 )δ (ppm) 102.3 (Ar``C 4 ), 112.0 (ArC 5 ), 118.5 (2C, Ar``C 2，6 ), 119.5 (CN), 122.2 (2C, Ar`C 2，6 ), 123.7 (ArC 6 ), 124.2 (ArC 7 ), 125.4 (Ar`C 4 ), 126.0 (ArC 9 ), 129.9 (2C, Ar`C 3，5 ), 132.6 (2C, Ar``C 3，5 ), 134.9 (ArC 8 ), 144.8 (Ar``C 1 ), 152.4 (ArC 10 ), 152.6 (Ar`C 1 ), 155.1 (ArC 2 ), 167.2 (ArC 4 ).

[0067] MS (ESI) m/z 337 (M + -1).

[0068]

[0069] The operation is as above. White flocculent solid, yield 86.6%; melting point: 220.6-220.8°C; 1 H NMR (DMSO-d 6 ) δ (ppm) 2.39 (s, 3H, CH 3 ), 7.26(d, 2H, J=8.8Hz, Ar``H 2，6 ), 7.33 (d, 2H, J=8.4Hz, Ar`H 3，5 ), 7.46(t, 1H, J=8.0Hz, ArH 7 ), 7.58 (d, 2H, J=8.4Hz, Ar`H 2，6 ), 7.70 (d, 1H, J=8.4Hz, ArH 6 ), 7.87 (td, 1H, J=8.0Hz, J`=1.6Hz, ArH 8 ), 7.94(d, 2H, J=8.8Hz, Ar``H 3，5 ), 8, 20 (dd, 1H, J=8.4Hz, J`=0.8Hz, ArH 9 ), 9.98(s, 1H, NH).

[0070] 13 C NMR (DMSO-d 6 ) δ (ppm) 20.5 (CH 3 ), 102.4 (Ar``C 4 ), 112.1 (ArC 5 ), 118.5 (2C, Ar``C 2，6 ), 119.5 (CN), 121.8 (2C, Ar`C 2，6 ), 123.7 (ArC 6 ), 124.2 (ArC 7 ), 125.4 (ArC 9 ), 130.2 (2C, Ar`C 3，5 ), 132.6 (2C, Ar``C 3，5 ), 134.8 (ArC 8 ), 135.1 (Ar`C 4 ), 144.9 (Ar``C 1 ), 150.1 (ArC 10 ), 152.5 (Ar`C 1 ), 155.1 (ArC 2 ), 167.2 (ArC 4 ).

[0071] MS (ESI) m/z 351 (M + -1).

[0072]

[0073] The operation is as above. Yellow needle-like solid, yield 79.4%; melting point: 218.6-220.2°C; 1 H NMR (DMSO-d 6 ) δ (ppm) 2.20 (s, 3H, CH 3 ), 7.51(t, 1H, J=7.6Hz, ArH 7 ), 7.61 (d, 2H, J=8.8Hz, Ar``H 2，6 ), 7.73-7.76 (m, 2H, Ar`H 5 +ArH 6 ), 7.88-7.94 (m, 4H, ArH 8 +Ar`H 5 +Ar``H 3，5 ), 8, 27 (d, 1H, J=8.0Hz, ArH 9 ), 10.09(s, 1H, NH).

[0074] 13 C NMR (DMSO-d 6 ) δ (ppm) 16.3 (CH 3 ), 102.6 (Ar``C 4 ), 111.2 (ArC 5 ), 117.6 (Ar`C 4 ), 118.5 (2C, Ar``C 2，6 ), 118.9(CN), 119.5(ArC 6 ), 123.6 (Ar`C 2 ), 124.5 (ArC 7 ), 125.6 (ArC 9 ), 132.7 (ArC 8 ), 132.8 (2C, Ar``C 3，5 ), 133.3 (Ar`C 3 ), 135.3 (Ar`C 5 ), 135.5 (Ar`C 6 ), 144.7 (Ar``C 1 ), 147.6 (ArC 10 ), 152.8 (Ar`C 1 ), 154.9 (ArC 2 ), 165.2 (ArC 4 ).

[0075] MS (ESI) m/z 511 (M + +1).

[0076] Example 3 Anti-HIV biological activity test

[0077] The anti-HIV virus activity at the cell level in vitro was determined by the Rega Institute of Pharmacy at Katholleke University in Belgium, mainly including two aspects: inhibitory activity and cytotoxicity to HIV-infected MT-4 cells. The method is as follows: make the compound in HIV-infected MT-4 cells, at different times of HIV infection, use the MTT method to measure the protective effect of the drug on HIV-induced cytopathy, and calculate that 50% of the cells are free from HIV-induced cytopathy half effective concentration IC 50 , Toxicity determination is carried out in parallel with anti-HIV activity experiment, also in MT-4 cell culture, the concentration that makes 50% uninfected cells take place cytopathic (CC 50 ), and calculate the selectivity index SI=CC 50 /IC 50.

[0078] Materials and Methods:

[0079] The anti-HIV activity of each compound is monitored by the inhibitory effect of the drug on the cytopathic effect caused by HIV in cells. MT-4 cells were used for cell culture. The virus strains used are: HIV-1 virus strain IIIB and HIV-2 virus strain ROD.

[0080] The specific operation is as follows: the compound is dissolved in DMSO or water and diluted with phosphate buffered saline solution, and 3×10 5 MT-4 cells were pre-incubated with 100 μL of the solutions of various concentrations of each compound at 37°C for 1 hour, then 100 μL of appropriate virus dilution was added to the compound, and the cells were incubated at 37°C for 1 hour. After three washes, cells were resuspended in culture medium with or without compound, respectively. Then place the cells in 5% CO 2 Incubate at 37°C for an additional 7 days in ambient air, and replace the supplemented medium with culture medium with or without compound on the third day post-infection. Each culture condition was repeated twice. The cytopathic effect on the virus was monitored daily using inverted light microscopy. Typically, the virus dilutions used in this experiment lead to cytopathic effects by day five after virus infection. Drug inhibitory concentration is the concentration at which the drug produces 50% inhibitory effect on viral cytopathic effects while having no direct toxicity to cells (CC 50 )express. It should be emphasized that when the compound has poor water solubility and needs to be dissolved with DMSO, the specific concentration of DMSO is generally lower than 10% relative to water (the final concentration of DMSO in MT-4 cell culture medium is less than 2%) . Because DMSO can affect the antiviral activity of the test compound, the antiviral activity comparison blank experiment containing the same concentration of DMSO solution should also be carried out in parallel. In addition, the final concentration of DMSO (1/1000) was much lower than that required to affect HIV-1 replication in T cells.

[0081] The present invention uses HEPT and DDI as reference substances, and the results of the inhibitory activity of some target compounds on HIV are shown in Table 1 (Anti-HIV Activity and Cytotoxicity of Compounds 1-32 in MT-4 Cells).

[0082]

[0083] Table 1

[0084]

[0085] a IC 50 : concentration of compound required to protect the cell against viral cytopathogenicity by 50% in MT-4 cells. b CC 50 : concentration of compound that reduces the normal uninfected MT-4 cell viability by 50%. c SI: selectivity index: ratio CC 50 /IC 50.

[0086] The experimental results show that the compounds contained in the general chemical structure formula generally have strong anti-HIV-1 virus activity, low cytotoxicity and high selectivity index.